the aging liver

TheThe Aging LiverAging LiverDr. Tarek ShetaDr. Tarek Sheta

Lecturer of internal medicineLecturer of internal medicineMansoura Faculty of MedicineMansoura Faculty of Medicine

TheThe Aging LiverAging LiverDr. Tarek ShetaDr. Tarek Sheta

Lecturer of internal medicineLecturer of internal medicineMansoura Faculty of MedicineMansoura Faculty of Medicine

Outline Normal Liver Morphological changes with aging Vascular changes with aging Metabolic changes with aging Relationship between liver disease and aging

Normal Liver Morphological changes with aging Vascular changes with aging Metabolic changes with aging Relationship between liver disease and aging

The Normal Liver…in briefLargest gland & ‘solid’ organ.

Up to 1.5kg in men & 1.3kg in women.

Holds up to 13% blood volume.

2 lobes; right 2/3rd > left 1/3rd

Largest gland & ‘solid’ organ.

Up to 1.5kg in men & 1.3kg in women.

Holds up to 13% blood volume.

2 lobes; right 2/3rd > left 1/3rd

The Normal Liver…in brief 2 distinct blood supplies

– Arterial – Hepatic arteries– Venous – Portal vein

2/3rd of liver is parenchymal; 1/3 isbiliary tract.

Average lifespan of a hepatocyte is ~150 days.

2 distinct blood supplies– Arterial – Hepatic arteries– Venous – Portal vein

2/3rd of liver is parenchymal; 1/3 isbiliary tract.

Average lifespan of a hepatocyte is ~150 days.

Effect of Aging on the liver

Unlike the heart, brain and kidneys, the liver isnot affected by common degenerativediseases such atherosclerosis, diabetes andhypertension.

The liver is spared these diseases probably asa result of its dual blood supply, abundantreserve and high regenerative capacity.

Unlike the heart, brain and kidneys, the liver isnot affected by common degenerativediseases such atherosclerosis, diabetes andhypertension.

The liver is spared these diseases probably asa result of its dual blood supply, abundantreserve and high regenerative capacity.

Morphological Changes of Ageing

Liver sizeThe liver has a remarkable ability to

regenerate and maintain functionduring the ageing process. There are,however, changes on a cellular andphysiological level which reduce theoverall function of the liver.

Liver sizeThe liver has a remarkable ability to

regenerate and maintain functionduring the ageing process. There are,however, changes on a cellular andphysiological level which reduce theoverall function of the liver.


Despite compensatory cell hypertrophy,in response to the decreased number ofhepatocytes seen with ageing, liver sizereduces by 25% between the age of 20and 70, with a 33% reduction of hepaticblood flow in over 65 year olds

Despite compensatory cell hypertrophy,in response to the decreased number ofhepatocytes seen with ageing, liver sizereduces by 25% between the age of 20and 70, with a 33% reduction of hepaticblood flow in over 65 year olds


The characteristicgross change thatoccurs in the agingliver is “brownatrophy”. Thedarkened colour isdue toaccumulation oflipofuscin pigmentwithin hepatocytes.

The characteristicgross change thatoccurs in the agingliver is “brownatrophy”. Thedarkened colour isdue toaccumulation oflipofuscin pigmentwithin hepatocytes.

Morphological Changes ↑ Lifespan of hepatocytes

↑ Nuclei size & polyploidy

↑ Mitochondrial volume

↑ Lifespan of hepatocytes

↑ Nuclei size & polyploidy

↑ Mitochondrial volume

Morphological Changes ↑ Intracellular protein

↑ Inter-hepatocyte space- (↑ collagen)

↑ Lipofuscin deposition- (↓ intracellular proteinolysis)

↑ Intracellular protein

↑ Inter-hepatocyte space- (↑ collagen)

↑ Lipofuscin deposition- (↓ intracellular proteinolysis)

Morphological Changes

At the microcirculatory level, liversinusoids demonstrate endothelialthickening and loss offenestrations, referred to aspseudocapillarisation.

At the microcirculatory level, liversinusoids demonstrate endothelialthickening and loss offenestrations, referred to aspseudocapillarisation.

Morphological Changes

Kupffer cells,important in the eliminationof endotoxin and tumour cells, suffer adecline in phagocytic function withaging.At the ultrastructural level, hepatocytes

demonstrate a decline in roughendoplasmic reticulum and mitochondria

Kupffer cells,important in the eliminationof endotoxin and tumour cells, suffer adecline in phagocytic function withaging.At the ultrastructural level, hepatocytes

demonstrate a decline in roughendoplasmic reticulum and mitochondria

Vascular Changes ↓ Liver blood flow (by ≤ 35%) [Normal =

~1.5L/min]

↓ Liver perfusion (≤ 10%)i.e. blood flow per unit vol. of liver tissue

↓ Liver blood flow (by ≤ 35%) [Normal =~1.5L/min]

↓ Liver perfusion (≤ 10%)i.e. blood flow per unit vol. of liver tissue

Response to InjuryThe liver is generally quite

tolerant of both acute andchronic insults. It is capable ofrecovering from interruption ofits blood supply andoxygenation for periods lastingone hour

The liver is generally quitetolerant of both acute andchronic insults. It is capable ofrecovering from interruption ofits blood supply andoxygenation for periods lastingone hour

Response to Injury

However, as the liver ages, itsability to regenerate after toxicinjury is impaired—theregenerative response iscomplete but it takes longer.

However, as the liver ages, itsability to regenerate after toxicinjury is impaired—theregenerative response iscomplete but it takes longer.

Response to InjuryThe reduced ability of the older liver

to regenerate may have an impacton the natural history of some liverdiseases.The rate of progression to cirrhosis

in patients with chronic hepatitis Cis directly associated with age atthe time of contracting the infection

The reduced ability of the older liverto regenerate may have an impacton the natural history of some liverdiseases.The rate of progression to cirrhosis

in patients with chronic hepatitis Cis directly associated with age atthe time of contracting the infection

Metabolic Changes ↓ Liver cholesterol synthesis

↓ Bile acid synthesis

↑ Secretion of cholesterol into bile

– ?? Latter two as possible cause for↑ gallstones with ageing

↓ Liver cholesterol synthesis

↓ Bile acid synthesis

↑ Secretion of cholesterol into bile

– ?? Latter two as possible cause for↑ gallstones with ageing

Metabolic Changes

No clinically significant change of LFTs– But minor & transient changes– E.g. in acute illness, heart failure

– In particular, mild ↑ Alkaline Phosphatase• ?? Acute phase protein response, if

transient rise• But if persistent, could indicate possible

liver dx.

No clinically significant change of LFTs– But minor & transient changes– E.g. in acute illness, heart failure

– In particular, mild ↑ Alkaline Phosphatase• ?? Acute phase protein response, if

transient rise• But if persistent, could indicate possible

liver dx.

Metabolic ChangesMinimal change to Blood Urea Nitrogen

– But urea synthesis is inverselyrelated to age

Minimal change to Blood Urea Nitrogen

– But urea synthesis is inverselyrelated to age

Hepatic Drug MetabolismThe hepatic elimination of galactose and

caffeine is significantly reduced in theelderly population.

A study of liver biopsies from a large,heterogenous population has shown agradual decline in the hepatocyteconcentration of P450 enzymes withage.

The hepatic elimination of galactose andcaffeine is significantly reduced in theelderly population.

A study of liver biopsies from a large,heterogenous population has shown agradual decline in the hepatocyteconcentration of P450 enzymes withage.

Hepatic Drug Metabolism

↓ Liver Enzyme Function

– Not due to ↓ enzyme deficiency

– Due to ↓ Liver blood flow

– Affects both Oxidative & Conjugativemetabolism

↓ Liver Enzyme Function

– Not due to ↓ enzyme deficiency

– Due to ↓ Liver blood flow

– Affects both Oxidative & Conjugativemetabolism


Consequent ↓ drug clearance– Up to 50% for some drugs

– Age alone might account for 10– 30%

– Other influencesDiet / Nutrition

Smoking

Consequent ↓ drug clearance– Up to 50% for some drugs

– Age alone might account for 10– 30%

– Other influencesDiet / Nutrition

Smoking

Specific liver diseases in theelderly

GENERAL RULESGENERAL RULES The presence of an advanced liver disease or

cirrhosis is more frequent in old patients asthe first clinical presentation.

No liver disease is specific to old age Onset is more insidious in older patients. Age-adjusted mortality is often greater in the

elderly.

GENERAL RULESGENERAL RULES The presence of an advanced liver disease or

cirrhosis is more frequent in old patients asthe first clinical presentation.

No liver disease is specific to old age Onset is more insidious in older patients. Age-adjusted mortality is often greater in the

elderly.

Specific Liver Diseases:Prevalence mildly ↑ with age

– Bacterialinfections(LiverAbscess)

– Primary BiliaryCirrhosis

– HepatocellularCarcinoma

– Non-Alcoholic Cirrhosis

– Obstructive Jaundice• Choledocholithiasis• Malignant

Obstruction

– Bacterialinfections(LiverAbscess)

– Primary BiliaryCirrhosis

– HepatocellularCarcinoma

– Non-Alcoholic Cirrhosis

– Obstructive Jaundice• Choledocholithiasis• Malignant

Obstruction

Viral hepatitis

HEPATITIS AAlthough hepatitis A is rare in

patients over 65 years of age theratio of mortality to notificationsrises dramatically withadvancing age.

HEPATITIS AAlthough hepatitis A is rare in

patients over 65 years of age theratio of mortality to notificationsrises dramatically withadvancing age.

HEPATITIS Bacute hepatitis B is rare in the

elderly population,Hepatitis B vaccination

produces a lower antibodyresponse with advancing age,possibly due to a lack ofantibody producing B cells.

acute hepatitis B is rare in theelderly population,Hepatitis B vaccination

produces a lower antibodyresponse with advancing age,possibly due to a lack ofantibody producing B cells.

HEPATITIS CSeveral studies of community

acquired hepatitis C, including ahigh proportion of elderly patients,suggest that it has a rather benigncourse.It seems likely that many elderly

individuals remain asymptomaticfrom HCV even if they may haveacquired it 20 or more years before.

Several studies of communityacquired hepatitis C, including ahigh proportion of elderly patients,suggest that it has a rather benigncourse.It seems likely that many elderly

individuals remain asymptomaticfrom HCV even if they may haveacquired it 20 or more years before.

Drug-induced liver injury

↑ Prevalence of drug-induced injury An important consideration in caring for

the elderly is the high incidence ofpolypharmacy and drug reactions in thisage group, so that in general, lowerdoses of hepatically- metabolised drugsare indicated compared to a younger agegroup.

↑ Prevalence of drug-induced injury An important consideration in caring for

the elderly is the high incidence ofpolypharmacy and drug reactions in thisage group, so that in general, lowerdoses of hepatically- metabolised drugsare indicated compared to a younger agegroup.

PRIMARY BILIARY CIRRHOSISamong initially asymptomatic

antimitochondrial antibody (AMA)positive patients, in elderlyindividuals, often picked up duringscreening for other autoantibodies,may show a particularly slow andindolent course.

among initially asymptomaticantimitochondrial antibody (AMA)positive patients, in elderlyindividuals, often picked up duringscreening for other autoantibodies,may show a particularly slow andindolent course.

Alcoholic liver disease There are important pharmacokinetic differences

in ethanol metabolism between older and youngersubjects.

most patients present with severe alcoholic liverdisease in their fifth or sixth decade.

Among those who do present to hospital withalcoholic liver disease over 60 years of age,symptoms are more severe with a higherfrequency of presentation with complications ofportal hypertension, and prognosis is directlyrelated to age.

There are important pharmacokinetic differencesin ethanol metabolism between older and youngersubjects.

most patients present with severe alcoholic liverdisease in their fifth or sixth decade.

Among those who do present to hospital withalcoholic liver disease over 60 years of age,symptoms are more severe with a higherfrequency of presentation with complications ofportal hypertension, and prognosis is directlyrelated to age.

AUTOIMMUNE HEPATITISgenerally affect younger women -

only 20% of cases of autoimmunehepatitis occur in patients olderthan 65 years.The prognosis in this age group is

excellent, as the disease generallyfollows a more benign course thatrarely leads to cirrhosis.

generally affect younger women -only 20% of cases of autoimmunehepatitis occur in patients olderthan 65 years.The prognosis in this age group is

excellent, as the disease generallyfollows a more benign course thatrarely leads to cirrhosis.

Gall Bladder stonesThere is a high prevalence of

gallstones among old people, inparticular among females.Complicated by diminished

perception of pain as well asrelative lack of physicalfindings.

There is a high prevalence ofgallstones among old people, inparticular among females.Complicated by diminished

perception of pain as well asrelative lack of physicalfindings.

Primary hepatocellularcarcinoma

At least in Western countries HCCmay be considered a diseaseassociated with aging.it has been demonstrated recently

that in an experimental model therewas a twofold increase in thenumber of DNA bases damaged byoxidative stress in advanced age.

At least in Western countries HCCmay be considered a diseaseassociated with aging.it has been demonstrated recently

that in an experimental model therewas a twofold increase in thenumber of DNA bases damaged byoxidative stress in advanced age.

Primary hepatocellularcarcinoma

HCC incidence had been low before age 40 asit increases progressively with older age andpeaks in incidence around ages 70–75.

The incidence of HCC drops steadily andsignificantly in individuals older than 75, andup to 90+.

Currently, with the rising rates of HCC, thereis a shift of incidence from typically elderlypatients to relatively younger patientsbetween ages 40 and 60 .

HCC incidence had been low before age 40 asit increases progressively with older age andpeaks in incidence around ages 70–75.

The incidence of HCC drops steadily andsignificantly in individuals older than 75, andup to 90+.

Currently, with the rising rates of HCC, thereis a shift of incidence from typically elderlypatients to relatively younger patientsbetween ages 40 and 60 .

Ascites There are no age-related absolute

contraindications to diuretics; however, someadverse effects may be more severe withadvancing age.

Elderly patients with cirrhosis are more likelyto suffer from disturbed fluid balancehomeostasis, leading to orthostatichypotension as a result of low intra-vascularvolume, exacerbated by diuretic use.

Furthermore, older patients prescribeddiuretics are at increased risk of incontinence.

There are no age-related absolutecontraindications to diuretics; however, someadverse effects may be more severe withadvancing age.

Elderly patients with cirrhosis are more likelyto suffer from disturbed fluid balancehomeostasis, leading to orthostatichypotension as a result of low intra-vascularvolume, exacerbated by diuretic use.

Furthermore, older patients prescribeddiuretics are at increased risk of incontinence.

Hepatic encephalopathy there are some pitfalls in making the

diagnosis of hepatic encephalopathy sinceother conditions can mimic the findings:

- Organic brain syndrome: eg cerebastherosclerosis.

- cognitive and memory impairment- delirium due to medication adverse events or

“polypharmacy” and drug interactions- uremia due to renal failure

there are some pitfalls in making thediagnosis of hepatic encephalopathy sinceother conditions can mimic the findings:

- Organic brain syndrome: eg cerebastherosclerosis.

- cognitive and memory impairment- delirium due to medication adverse events or

“polypharmacy” and drug interactions- uremia due to renal failure

Hepatic encephalopathyCare should be taken when

treating the elderly withlaxatives; malabsorption,dehydration, electrolyteimbalance and faecalincontinence are all more likelyto occur

Care should be taken whentreating the elderly withlaxatives; malabsorption,dehydration, electrolyteimbalance and faecalincontinence are all more likelyto occur

Fulminant Hepatitismortality after fulminant hepatic

failure is higher in the agedpopulation regardless of theetiology of the hepatic injury,

mortality after fulminant hepaticfailure is higher in the agedpopulation regardless of theetiology of the hepatic injury,

- Advanced age is not considered acontraindication to livertransplantation- but recipients older than 60 yearswith poor hepatic synthetic functionand comorbidity show a worseprognosis with lower survivalrates.

Liver Transplantation

- Advanced age is not considered acontraindication to livertransplantation- but recipients older than 60 yearswith poor hepatic synthetic functionand comorbidity show a worseprognosis with lower survivalrates.

Liver Transplantationlivers from older donors that are

transplanted into hepatitis Cinfected recipients are more likelyto be damaged by the viruscompared to younger grafts.

livers from older donors that aretransplanted into hepatitis Cinfected recipients are more likelyto be damaged by the viruscompared to younger grafts.

Liver TransplantationIt has been suggested that the

marginal impairment of immunefunction accompanying normalaging may reduce the incidence ofallograft rejection and may allowlower dosage ofimmunosuppressive drugs in olderliver recipients.

It has been suggested that themarginal impairment of immunefunction accompanying normalaging may reduce the incidence ofallograft rejection and may allowlower dosage ofimmunosuppressive drugs in olderliver recipients.

Liver resection

Age did not influence morbidity, in-hospital mortality and survival ofpatients undergoing hepatectomy.

the aging liver

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